Abstract
Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine.In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.
Highlights
High-throughput metabolomics experiments using mass spectrometry platforms are becoming an integral part of clinical and systems biology research
Human metabolite levels differ between individuals due to environmental and genetic factors
Thereby, we discovered six novel regions in the genome and confirmed ten regions previously found to be associated with metabolites in plasma, serum or urine. We analyzed whether these variants regulate gene-expression in peripheral mononuclear cells and at several loci we identified novel causal relations between SNPs, gene-expression and metabolite levels. These findings help explaining the functional mechanisms by which associated genetic variants regulate metabolism
Summary
High-throughput metabolomics experiments using mass spectrometry platforms are becoming an integral part of clinical and systems biology research. Profiling of amino acids and acylcarnitine species in dried whole blood samples of newborns is used worldwide in neonatal screening programs to identify rare inborn errors of metabolism [1]. These diseases are generally caused by rare mutations, leading to loss of function of an enzyme that catalyzes the biochemical reaction of the respective trait. Amino acids and acylcarnitines show substantial inter-individual variation [6] and a strong genetic contribution to their blood concentrations has been reported [7]. The integration of genetic and metabolic profiling holds the promise for providing novel insights into the regulation of metabolic homeostasis in health and disease
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